HU221301B1 - Amino-benzoic acid derivatives, process for producing them and pharmaceutical preparatives containing them - Google Patents

Abstract

The present invention relates to aminobenzoic acid derivatives of the formulas I, I-2 and I-3 and their pharmaceutically acceptable salts. In the formula (I), R 1 is C 3 -C 8 alkynyl, cyano (C 1 -C 5) alkyl, C 1 -C 5 alkyl substituted by halogen, or C 3 -C 8 cycloalkyl substituted by C 1 -C 5 alkoxy, R 2 is amino; or (C 2 -C 5) alkanoyl-amino, R 3 is -halogen, R 1, R 2 and R 3 in formula I-2 are substituted and R 4 is C 1-7 -alkyl, in formula (I-3) R1, R2 and R3 are as defined, with the proviso that R1 is other than trifluoromethyl. The present invention relates to a process for the preparation of amino-benzoic acid derivatives having an amino group at the R 2 position of the compounds of the formula I and to pharmaceutical compositions containing the compounds of the formula I. The compounds are serotonin antagonists and acetylcholine release agents are accelerating. ŕ

Description

The invention relates to a method and pharmaceutical compositions containing the compounds of formula (I) for the amino acid derivatives of compounds of formula (I), R ² amino group in place thereof. The compounds are serotonin antagonists and have the effect of accelerating the release of acetylcholine.

The length of the description is 40 pages (including 21 pages)

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The present invention relates to aminobenzoic acid derivatives, in particular to aminobenzoic acid derivatives as pharmaceutical active ingredients, to processes for their preparation and to pharmaceutical compositions containing them.

The percentage of patients who are constantly growing and now account for 60% or more of people who have unidentifiable complaints such as abdominal complaints such as heartburn, nausea, nausea and vomiting.

These unidentifiable complaints result from functional abnormalities in the digestive system. For example, in patients with unidentifiable gastrointestinal complaints, such as chronic gastritis, gastric emptying is delayed, whereas in patients with unidentified lower abdominal complaints, such as hypersensitive bowel syndrome, with abdominal emptying being the main symptom, in.

Stress and anxiety have been shown to be the cause of unidentifiable complaints, and in this sense, it is clear that unidentifiable complaints are one of the modem diseases.

To reduce the aforementioned unidentifiable gastrointestinal complaints, dopamine antagonists, musculotropic agents are used to control smooth muscle movement, and acetylcholine releasing accelerators are also used. Dopamine antagonists cause side effects, causing Parkinson's disease, and should be used with caution, musculotropic agents that regulate smooth muscle movement also cause side effects such as constipation, and acetylcholine releasing accelerating against nausea, so their application is unsatisfactory.

Studies have been conducted to develop an agent that is capable of treating patients with unidentifiable gastrointestinal complaints without adversely affecting side effects while reducing anxiety, which is usually one of the causes of symptoms in such patients.

It has been found that an agent having both serotonin (hereinafter referred to as "5HT ₃ ") antagonism and acetylcholine (hereinafter referred to as "ACh") release activity fulfills the above requirements. Therefore, studies have been conducted to find compounds that have both effects and have been found to be the aminobenzoic acid derivatives of formula (I) and their pharmaceutically acceptable salts.

Aminobenzoic acid derivatives useful as pharmaceutical active ingredients are disclosed in British Patent Publication No. 1593146/1981 (Beecham Group Ltd., published July 15, 1981), in British Patent Publication No. 2125398/1984 (Donatsch). P; Sandoz AG; Sandoz-Patent GmbH; and Sandoz SA, published March 7, 1984; and British Publication No. 2205095/1980 (Bristol-Myers Squibb Co. and Bristol-Myers Co., published 1988). U.S. Patent No. 4,797,406/1985 to Sandoz-Patent GmbH; and Sandoz SA, published April 24, 1985; and U.S. Patent No. 5,511,331/1991, to Sandoz AG, published November 1991, U.S. Pat. European Patent Publication No. 189002/1986 (Sandoz AG, published July 30, 1986); European Patent Publication No. 220011/1987, published by Beecham Group PLC. European Patent Publication No. 302699/1989 (Fordonal SA and Walton SA, published February 8, 1989), and British Patent Application No. 2169292/1988 (Sandoz Ltd., published by: September 21, 1988), the compounds of the present invention differ in structure from these compounds.

The present invention relates to aminobenzoic acid derivatives of the general formulas (I), (1-2) and (1-3) and their pharmaceutically acceptable salts.

In the general formula (I)

R ¹ is C 3 -C 8 alkynyl, cyano (C 1 -C 5) alkyl, C 1 -C 5 alkyl substituted by halogen, or C 3 -C 8 cycloalkyl substituted by C 1 -C 5 alkoxy,

R ² is amino or (C 2 -C 5 alkanoyl) amino;

R ³ is halogen, with the proviso that R ¹ is other than trifluoromethyl.

In the formula (1-2), R ¹ , R ² and R ³ are as defined and R ⁴ is C 1 -C 7 alkyl, provided that R ¹ is other than trifluoromethyl.

In the formula (1-3), R ¹ , R ² and R ³ are as defined, provided that R ¹ is other than trifluoromethyl.

Specific examples of the aminobenzoic acid derivatives of the invention include the following:

(1) compounds of formulas (I), (1-2) and (1-3), provided that R ¹ is C 3-8 alkynyl;

(2) Compounds of formula (I), (1-2) and (1-3), with the proviso that R ² is amino.

(3) Compounds of formula (I), with the proviso that R ¹ is cyano (C 1 -C 5) -alkyl, (C 3 -C 8) -cycloalkyl (C 1 -C 5) -alkoxy, (C 1 -C 5) -halogen (C 1 -C 5) alkyl or C 3-8 alkynyl;

(4) Compounds of formula (II) wherein

R ' _a is C 3 -C 8 alkynyl,

R ² is amino or (C 2 -C 5) alkanoyl-amino;

R ³ is halogen.

(5) compounds of formula (1-2) and (1-3), and (6) compound of formula (1-3-1).

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Specific examples of pharmaceutically acceptable salts of the aminobenzoic acid derivatives of the present invention include:

(1) the pharmaceutically acceptable salts of the compounds mentioned in (1) to (6) above, and (2) the compound of the formula (1-2-1).

The compounds of formula (I) - wherein R ^1, R ² and R ³ are as defined - was prepared (III) or of formula (XI) compounds wherein R ³ is as defined above and Ac is an acetyl group, and Q represents a lower alkyl, halo-substituted lower alkyl, arylalkyl, arylalkenyl or aryl. Compounds of formula (111) may be prepared by known methods from J. Labeled Compound Radiopharm., 23 (3), 245-256 (1986), US-A 4863921, DE-A 3643103, DE-A 3620215, U.S. Pat. US-A 4284644, EP-A 18830, EP-A 3084, FR-A 6817 and FR-A 1539104.

The compounds of formula (XI) may be prepared in a known manner as described in J. Med. Chemical, 1990, 33 (5), 1406-13, US-A 4863921 and FR-A 1539104.

The quatemerammonium compound of formula (1-2), wherein R ¹ , R ² , R ³ and R ⁴ are as defined, can be prepared from a tertiary amine by known methods, for example by reacting the amine in a solvent with or without a base with an alkylating agent. The base may be, for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. The alkylating agent may be, for example, a C 1-7 alkyl halide such as methyl iodide, dimethyl sulfate, C 1-7 alkyl sulfonate or C 6-14 aryl sulfonate. Suitable solvents are dimethylsulfoxide, Ν, Ν-dimethylformamide, tetrahydrofuran, diethyl ether, acetonitrile, chloroform, dichloromethane, ethanol, methanol, benzene or toluene. The reaction temperature is -100 to 200 ° C, preferably 0 to 150 ° C.

The N-oxide compound (I-3) can be prepared from a tertiary amine compound in a known manner with an oxidizing agent in a solvent. The oxidizing agent may be m-chloroperbenzoic acid, hydrogen peroxide, potassium peroxy monosulfate, periodic acid, dimethyldioxirane or benzoyl peroxide. The solvent may be dimethyl sulfoxide, N, N-dimethylformamide, tetrahydrofuran, diethyl ether, acetonitrile, chloroform, dichloromethane, ethanol, methanol, benzene or toluene. The reaction temperature is -100 to 100 ° C.

The present invention also relates to pharmaceutical compositions for the prophylaxis or treatment of a disease which results in a serotonin antagonism or acetylcholine release accelerating action in the disease state, and which are active compounds of the present invention (I), (1-2) or (1-3). or a pharmaceutically acceptable salt thereof.

The present invention also relates to compositions which increase gastrointestinal function, such as gastric emptying, and further relates to vomiting, anti-nausea, agents for the prevention and treatment of hypersensitivity bowel syndrome, amnesic syndrome, senile dementia, Alzheimer's disease. and compositions for the prevention and treatment of addiction, comprising as active ingredient the aminobenzoic acid derivatives of the present invention or pharmaceutically acceptable salts thereof.

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of the aminobenzoic acid derivatives or pharmaceutically acceptable salts thereof.

The present invention relates to the use of the aminobenzoic acid derivatives or pharmaceutically acceptable salts thereof according to the invention in the preparation of a medicament for the treatment of diseases which can be treated by serotonin antagonism or acetylcholine release accelerator.

The method of treatment of the present invention comprises administering to a patient suffering from a disease which can be treated by serotonin antagonism or acetylcholine release accelerating agent a therapeutically effective amount of the aminobenzoic acid derivative or a pharmaceutically acceptable salt thereof.

The present invention will now be understood from the detailed description.

(I), (1-2) and (1-3) wherein ^R1 report on the halogen substituted C 1-5 alkyl the alkyl Exemplary of the following: methyl, ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl, tert-butyl, pentyl, (amyl), isopentyl, neopentyl, terepentyl, 1-methylbutyl; 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl. In the C 1 -C 5 alkyl substituted by halogen, the halogen may be fluorine, chlorine, bromine or iodine, and the number of substituent halogens is preferably 1-3, with the proviso that R ¹ is other than trifluoromethyl. The halogen atom can be attached to any carbon atom of the lower alkyl group.

In the meaning of R ¹ , the alkyl group of the cyanoalkyl group may be the alkyl group described above for the C 1 -C 5 alkyl group substituted by halogen (hereinafter referred to as "lower alkyl group" as defined above). The cyano group may be attached to any carbon atom of the alkyl group.

In R ', the alkynyl group may be derived from a C3-C8 alkyl group in which one or more carbon-carbon single bonds are substituted by a triple bond, and these triple bonds may be located at any position. By way of example, the following alkynyl groups are mentioned:

-CH-CH ₂ -C ^ CH, -CH-C = C 11, -ch-c = c-ch ₃

III ch ₃ c ₂ h ₅ ch ₃

-ch ₃ -c = ch, -ch ₂ ch ₂ c = c-ch ₃ , -ch ₂ c = c-ch ₃ ,

I ch ₃

-ch ₂ ch ₂ c = ch, -ch ₂ c = ch, -ch-c = c-ch ₃ ,

I c ₂ h ₅

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-CH-C = CC ₂ H ₅ , -CH-CH ₂ C = CC ₂ H ₅ ,

II ch ₃ ch ₃

-CH-OC-CC ₂ H ₅₎

I

C ₂ H ₅

-CC = CH, -CH-C ^ CH 1 CH ₃

CH ₃ CH ₃ CH ch ₃

Particularly preferred alkynyl groups are -CH-C = C-CH ₃ , -CH-ChCH or

II ch ₃ c ₂ h ₅

-CH-CH2 ₊ = CH.

I ch ₃

Where ^R2 include lower alkanoyl groups include alkanoyl amino group as an example, such as formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl and pivaloyl.

In R ³ , halogen may be fluorine, chlorine, bromine or iodine, preferably chlorine.

For example, the alkyl group in R ⁴ may be lower alkyl as defined above for R ¹ .

The pharmaceutically acceptable salts of the present invention include inorganic salts such as hydrochlorides, hydrobromides, sulfates and phosphates, organic salts such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates, toluenesulfonates; and amino acid salts such as arginates, aspartates and glutamates.

The aminobenzoic acid derivatives of the invention may also form metal salts such as sodium, potassium, calcium or magnesium salts or may be present in the form of hydrates. According to the invention, pharmaceutically acceptable salts include metal salts and hydrates.

The compounds of the invention may be present as geometric isomers and optical isomers, all of which are within the scope of the present invention.

Preferred compounds of the invention are described below. The most preferred compounds correspond to formula (II): wherein R'a represents a C3-8 alkynyl group and R ² and R ³ are as defined above.

R ^{3 is} particularly preferably chlorine.

R 'is _the particular and preferred alkynyl groups are as follows:

-CH-C = C-CH ₃ , -ch-cch, -ch-ch ₂ c = ch.

III ch ₂ c ₂ h ₅ ch ₃

The compounds of the present invention are serotonin antagonist and acetylcholine release accelerators. Serotonin antagonism refers to 5-HT3 antagonism.

A particularly preferred compound of the invention is (-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(3- pentin-2-yl} oxy} benzamide hydrochloride.

A compound of formula (I), (1-2) and (1-3) are those wherein R ² is amino can be produced by the amino-benzoic, or pharmaceutically acceptable salts thereof (a) is obtained.

The compound of formula (a) is an intermediate of the 4-amino substituted compounds of formula (I), (1-2) and (1-3). Thus, this compound can be used as starting material for the synthesis of said compounds of formulas (I), (1-2) and (1-3).

And pharmaceutically acceptable salts thereof of the present invention (I) are those wherein R ² is amino can be prepared by reacting a compound of formula (a), wherein

R ³ is as defined for and

R ⁵ is C 3 -C 8 alkynyl, cyano-C 1 -C 5 alkyl, C 1 -C 5 alkyl substituted by halogen, or C 3 -C 8 cycloalkyl substituted by C 1 -C 5 alkoxy, with the proviso that or a reactive derivative of a compound other than a is condensed with a compound of formula IX and, if desired, the resulting compound of formula I is converted into a pharmaceutically acceptable salt thereof.

In the formula (a), R ³ is a halogen atom,

R ⁵ is C 3 -C 8 alkynyl, cyano (C 1 -C 5 alkyl), C 1 -C 5 alkyl substituted with halogen, or C 3 -C 5 cycloalkyl optionally substituted with C 1 -C 5 alkoxy.

The compounds of formula (a) are novel compounds. Particularly preferred compounds of formula (a) are the following and pharmaceutically acceptable salts thereof:

4-Amino-5-chloro-2 - {(3-pentin-2-yl) oxy} benzoic acid, 4-amino-5-chloro-2 - {(1-pentin-4-yl) oxy} - benzoic acid, 4-amino-5-chloro-2 - {(1-pentin-3-yl) oxy} benzoic acid, 4-amino-5-chloro-2 - {(3-butyn-2-yl) oxy } benzoic acid, 4-amino-5-chloro-2 - {(2-hexin-4-yl) oxy} benzoic acid, and 4-amino-5-chloro-2 - {(1-hexin-3-yl) ) oxy} benzoic acid.

The compound of formula (a) may be present as geometric and optical isomers. If the final product of formulas (I), (1-2) and (1-3) is an optically active compound, the starting compound is an optically active compound (a) or a racemic compound (a) can be used as the starting compound and one of the syntheses step (a) is performed with optical resolution.

Methods for preparing the compounds of the invention are described below.

Production Method 1

R ² is prepared a compound of formula having an amino group (I) as follows:

The first step of the reaction is carried out as shown in Scheme 1-1, wherein R ¹ and R ³ are as defined above.

Q is lower alkyl, halo-lower alkyl, arylalkyl, arylalkenyl or aryl; Z is halogen and Ac is acetyl.

In this step, a compound of formula (IV) is prepared by reacting a compound of formula (III) with a compound of formula (V) or (VI).

The solvent is preferably Ν, Ν-dimethylformamide or dimethylsulfoxide in the reaction of the compounds of formula (III) and (V).

The reaction temperature is preferably 0 to 100 ° C and the reaction time is 30 minutes to 3 hours.

The reaction of the compound of formula (III) with the compound of formula (VI) is carried out by reacting triphenylphosphine with azodicarboxylate in a solvent such as tetrahydrofuran or benzene, or in a solvent in an inert gas atmosphere, preferably at -80 to 0 ° C. and then adding a solution of the compound of formula VI in tetrahydrofuran and a solution of the compound of formula III in tetrahydrofuran and reacting the resulting mixture for 30 minutes to several hours while allowing the temperature to rise to room temperature, and The compounds of formula (IV) are thus prepared.

The second step of the reaction is illustrated in Scheme (1-2). In the formulas, R ¹ , R ³ , Q and Ac are as defined.

In this step, the compound of formula IV prepared in the first step is deacetylated. Preferably, sulfuric acid is used in equivalent amounts or in excess.

An especially preferred solvent for the reaction is an alcoholic solvent such as methanol or ethanol.

The reaction temperature is preferably from about 0 ° C to about 50 ° C.

The third step of the reaction is illustrated in Scheme (1-3). In the formulas, R ¹ , R ³ and Q are as defined above.

In this step, the compound of formula VII prepared in step 2 is hydrolyzed.

Hydrolysis is carried out in the presence of two or more equivalents of a strong base such as sodium hydroxide or potassium hydroxide in an alcoholic solvent such as methanol or ethanol at room temperature to 100 ° C for several hours to prepare the compound of formula VIII. compounds.

Step 4 of the reaction is illustrated in Scheme 1-4, wherein R ¹ , R ³ are as defined.

In this step, the compound of formula (I) 'is prepared by condensing the compound of formula (VIII) obtained in step 3 with the 3-aminotropane of formula (IX).

3-Aminotropan of formula (IX), 3α-aminotropane or 3 [beta] -aminotropane may be prepared by known methods, for example, according to the method described in the Journal of the American Chemical Society (J. Am. Chem. Soc., 79, 4194 (1957)). .

The condensation reaction is conducted in the presence of a suitable dehydrating agent such as a carbodiimide such as dicyclohexylcarbodiimide. The reaction may also be carried out by reacting a compound of formula VIII with a reactive derivative such as an acid anhydride or a mixed acid anhydride (an acid anhydride containing an appropriate portion of a compound of formula VIII and another carboxylic acid), an acid azide, N-hydroxy is converted into the active ester or acid chloride with benzotriazole-N-hydroxysuccinimide (a mixture of the two compounds) and the resulting reactive derivative is reacted with the compound of the formula IX.

The reactions may be carried out in the absence or in the presence of a solvent, such as benzene, toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride, N, N-dimethylformamide and pyridine.

When the reaction is carried out in a solvent, an inorganic base such as sodium bicarbonate, potassium carbonate, sodium carbonate or sodium hydroxide or an organic base such as triethylamine or pyridine is used. so we get better results.

Production Method 2

R ² is (1) compounds having an amino group can also be prepared as follows.

The first step of the reaction is illustrated in Scheme (2-1). In the formulas, R ¹ , R ³ , Z and Ac are as defined.

In this step, a compound of formula (XII) is prepared by reacting a compound of formula (XI) with a compound of formula (V) in the presence of a base for several hours.

The base is preferably potassium carbonate or sodium carbonate, but any other base may be used.

Any solvent used in the reaction may be used provided the reaction is intimate.

The reaction temperature is preferably from about 0 ° C to about 100 ° C.

The second step of the reaction is illustrated in Scheme (2-2).

In the formulas, R ¹ , R ³ and Ac are as defined.

In this step, the compound of formula (XII) obtained in step 1 is deacetylated to give the compound of formula (XIII).

The deacetylation can be carried out in a known manner, for example by reacting a compound of formula XII with sulfuric acid and an equivalent or excess amount of a solvent such as methanol or ethanol for several hours.

The reaction temperature is preferably from about 0 ° C to about 50 ° C.

The third step of the reaction is illustrated in Scheme (2-3). In the formulas, R ¹ and R ³ are as defined.

The compound of formula (XIII) prepared in step 2 is hydrolyzed.

The hydrolysis may be carried out in a manner known per se, e.g.

By reacting with 2 or more equivalents of a strong base such as sodium hydroxide or potassium hydroxide at room temperature to 100 ° C for several hours.

Step 4 of the reaction is illustrated in Scheme (2-4). In the formulas, R ¹ and R ³ are as defined.

In this step, the compound of formula (I) 'is prepared in the same manner as in step 4 of the first production process.

Production Method 3

Compounds of formula (I) wherein R ² is different from amino and have substituents as defined for R ² may be prepared as follows:

The first step of the reaction is illustrated in Scheme (3-1). Wherein R ^1, R ³ and Q are the same as defined, and R ^2a is an amino group R ² as defined above report.

In this step, a compound of formula (VII) is acylated to a compound of formula (XIV) in a known manner.

The acylation of the compound of formula VII may be carried out, for example, by reacting the compound of formula VII with a suitable acylating agent such as an acid chloride or an anhydride, or by acylation in the presence of a suitable dehydrating agent such as a carbodiimide such as dicyclohexylcarbodiimide. a reactive derivative containing a desired acyl group, i.e. a reactive derivative of a compound of formula VII, such as an azide, a mixed anhydride (containing the corresponding portion of a compound of formula VII and another carboxylic acid) or N-hydroxybenzotriazole with N-hydroxysuccinimide or an active ester of another compound, and treating the resulting reactive derivative.

The acylation may be carried out in the absence of a solvent or in a solvent inert to the reaction. Examples of the solvent include benzene, toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride, Ν, Ν-dimethylformamide and pyridine.

In some cases, better results may be obtained by acylation in the presence of an inorganic base such as sodium bicarbonate, potassium carbonate, sodium carbonate or sodium hydroxide or an organic base such as triethylamine or pyridine.

The second step of the reaction is illustrated in Scheme (3-2). In the formulas, R ¹ , R ³ , Q and R ^2a are as defined.

In this step, the compound of formula (XIV) prepared according to the first step is hydrolyzed.

Hydrolysis is carried out in a known manner, for example, by treating a compound of formula (XIV) in a solvent such as methanol or ethanol for two hours in the presence of two or more equivalents of a base such as sodium hydroxide or potassium hydroxide. .

The reaction temperature is preferably from room temperature to about 100 ° C.

The third step of the reaction is illustrated in Scheme (3-3). In the formulas, R ¹ , R ³ and R ^2a are as defined.

In this step, the compound of formula (1) 'is prepared by condensing the compound of formula (XV) obtained in step 2 with the 3-aminotropane of formula (IX).

The condensation reaction is conducted in the presence of a suitable dehydrating agent such as a carbodiimide such as dicyclohexylcarbodiimide. The condensation can also be carried out by reacting a compound of formula XV with a reactive derivative such as an acid anhydride, a mixed acid anhydride (a compound corresponding to a compound of formula XV and another carboxylic acid), acid azide, N-hydroxybenzotriazole-N-hydroxy is converted to the active ester formed with a similar compound, the acid chloride, and the resulting reactive derivative is condensed with the compound of formula (IX).

These reactions can be carried out in the absence or presence of a solvent in a solvent such as benzene, toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride, N, N-dimethylformamide or pyridine.

When the reaction is carried out in a solvent, an organic base such as sodium bicarbonate, potassium carbonate, sodium carbonate or sodium hydroxide or an organic base such as triethylamine or pyridine is also used to give better results.

Production Method 4

Compounds of formula (I) wherein R ² is different from amino and have substituents as defined in R ² may also be prepared as follows.

The first step of the reaction is illustrated in Scheme (4-1). In the formulas, R ¹ , R ³ , A and R ^2a are as defined.

In this step, the compound of formula XIII is acylated or alkylated to the compound of formula XVI as described in the first step of Production Method 3.

The second step of the reaction is illustrated in Scheme (4-2). In the formulas, R ¹ , R ^2a and R ³ are as defined.

In this step, the compound of formula (XVI) obtained in the first step is hydrolyzed to the compound of formula (XV) as described in the second step of Production Method 3.

The third step of the reaction is illustrated in Scheme (4-3). In the formulas, R ¹ , R ^2a and R ³ are as defined.

In this step, the compound of formula (1) 'is prepared by condensation of the compound of formula (XV) prepared in the second step with the 3-aminotropane (IX) as described in the third step of Production Method 3.

Production Method 5

The general formula (I) for substituents other than an amino group at the R ² position in the definition of R ²

The compounds of formula (I) can also be prepared as follows.

The first step of the reaction is illustrated in Scheme 5-1. In the formulas, R ^{1 *} , R ^2a and R ³ are as defined.

In this step, a compound of formula VIII is acylated to a compound of formula XV.

The acylation of the compound (VIII) may be carried out by reacting the compound (VIII) with a suitable acylating agent such as an acid chloride or an anhydride, or the acylation may be carried out in the presence of a suitable dehydrating agent such as a carbodiimide such as dicyclohexylcarbodiimide. ), a reactive derivative of a compound of formula (VIII) may be prepared, for example, with an acid ester, a mixed anhydride (a compound containing the appropriate portion of a compound of formula VIII and another carboxylic acid) or an active ester of N-hydroxybenzotriazole-N-hydroxysuccinimide and reacting the resulting reactive derivative.

The aforementioned acylation procedures can be carried out in the absence of a solvent or in a solvent inert to the reaction. Examples include benzene, toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride, Ν, Ν-dimethylformamide and pyridine.

Good results can be obtained if the aforementioned reactions are carried out in the presence of an inorganic base such as sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide or an organic base such as triethylamine or pyridine.

The second step of the reaction is carried out according to Scheme 5-2. In the formulas, R ¹ , R ^2a and R ³ are as defined.

In this step, the compounds of formula (1) 'are prepared by condensing the compound of formula (XV) obtained in the first step with the 3-aminotropane of the formula (IX) in a manner analogous to the third step of Preparation 3 or 4.

The preparation methods described above are described in

Scheme I is illustrated below.

Experimental examples

The following experimental examples illustrate the efficacy of the compounds of the invention.

Experimental Example 1

Antagonism of 2-methyl-serotonin-induced ileum shrinkage or contraction The experiment was performed by Sanger et al., Eur. J. Pharmacol., 159, 113-114 (1989)]. The non-terminal ileum of male Hartley guinea-pigs was suspended in Krebs-Henseleit solution (37 ° C) using a 0.5 load on the ileum and a gas mixture containing 95% oxygen and 5% carbon dioxide was passed through the solution. The contraction of the ileum is determined isometrically. The ileum is allowed to stand for one or more hours for stabilization, and then a solution of the test compound is added to the solution and, after 30 minutes, a non-cumulative amount of 2-methyl-serotonin is added.

The pA2 value is calculated from the right shift of the dose response curve of the 2-methyl serotonin-induced contraction induced by the test compound, Rossum et al., Arch. Pharmacodyn., 143, 299 (1963)]. BRL 24682 was used as a control in the experiment.

The results are shown in Table 1.

Table 1

Test compound (number of example) pA 2 Second 8.68 4. (-) - Isomer 8.57 36. (+) - Isomer 8.72 38. (+) - Isomer 9.02 21st 8.46 25th 9.05 26th 9.33 27th 9.39 29th 9.34 32nd 9.03 42. (+ [- isomer 8.92 BRL 24682 7.80

Comparative studies were carried out with the compounds of the invention and the compounds of EP-B-554 794. The results are shown in Table 1A.

1A. spreadsheet

The test compound pA 2 Relative efficacy Compound of Formula 51 EP-B-554 794 7.81 Shoot Compound 52 EP-B-554 794 7.98 1.5 Compound 21 8.46 4.5 Compound (2) 8.68 7.4 Compound 4 8.57 5.8 Compound 36 8.72 8.1

The results show that the compounds of the invention are much more potent than the reference compounds.

Experimental Example 2

Efficacy against Cis-Platinum-Induced Vomiting in Dogs

Hunting dogs weighing 7-12 kg are used. Cisplatin (product of Sigma) (1 ml / kg physiological saline) is added to the anterior vein of each dog. One hour after cisplatin administration, physiological saline (0.2 mL / kg) was added to the control

A solution of the test compound in physiological saline solution is administered to the members of the hunting dog group and then to the dogs in the test group, into the vein of the other hind foot. The density of the vomiting was assayed for 5 hours after the administration of cis-platinum, and the inhibitory effect of the test compounds was calculated by the following formula.

The results are shown in Table 2.

average frequency in the study group

Inhibition rate (%) = 1 - átlagos 100 mean frequency in the control group

Table 2

Test compound (number of example) Inhibition of Cis-Platinum-Induced Vomiting (%) 0.03 mg / kg 0.1 mg / kg 0.3 mg / kg 4. (-) - Isomer 37 78 21st 100 42. (+) - Isomer 59 92

Experimental Example 3

Effect on increasing gastric emptying function The study was performed by Decktor et al., Eur. J. Pharmacol. 147: 313-316 (1988). Male Fischer rats (weighing 160-180 g) were fasted for 18 hours and then 3 ml of test food was administered orally to each rat. This diet contains methyl cellulose, beef broth, casein, sugar and wheat starch. The stomach is removed 1 hour after dosing. The clearance effect is calculated from the weight of test food remaining in the stomach. The increase in gastric emptying function was calculated by comparing the gastric emptying rate of the drug-treated rat with that of the control rats not treated with the test compound. Test compounds are administered orally (5 ml / kg) 1 hour before the test diet. BRL 24682 was used as a control in the experiment.

The results are shown in Table 3.

Table 3

Test compound (Example number) Increase in gastric emptying function (%) Second 24.5 4. (-) - Isomer 31.1 37. (-) - Isomer 15.3 38. (+) - Isomer 20.5 21st 18.9 24th 13.2 25th 26.3 27th 17.2

Test compound (Example number) Increase in gastric emptying function (%) 29th 20.6 32nd 18.3 40. racemic form 16.2 42. (+) - Isomer 22.2 43. (-) - Isomer 12.9 BRL 24682 12.9

Experimental Example 4

Effect on increase in contraction of guinea pig ileum induced by electrical stimulation

The experiment was performed by Sanger et al., Br. J. Pharmacol., 91, Tl% 1 (1987)]. Longitudinal muscles of guinea pig non-terminal ileum were separated and suspended vertically in Krebs-Henseleit solution (37 ° C) using a 0.5 g load at the end of the muscles in a Magnus tube. A gas mixture containing 95% oxygen and 5% carbon dioxide was passed through the solution. Muscle contraction is determined isometrically. Applying a platinum electrode to the muscles gives an electric field stimulation once for 1 second to induce contraction of the muscles. The contraction is triggered by the release of acetylcholine. After muscle stabilization, the test compound solution is added cumulatively to the Magnus tube every 10 minutes. The effect of the test compound is expressed as a percentage of the initial contraction. The minimum concentration of each test compound at which the rate of contraction as a result of the release of acetylcholine is observed is determined. The results are shown in Table 4.

Table 4

Test compound (number of example) Minimum Concentration that Causes Increased Ileolar Tension (umol) 21st 0,052 46th 0.16 22nd > 100 23rd > 100 24th 0.17 20. racemic form 0.11 37. (+) - Isomer 0,048 38. (-) - Isomer 0.13 2. racemic form 0.05 4. (+) - Isomer 0,056 36. (-) - Isomer 0.26 40. racemic form 0.22 42. (+) - Isomer 0.086 43. (-) - Isomer 0.47

HU 221 301 Β1

Table 4 (continued)

Test compound (number of example) Minimum concentration that causes an increase in ilcum contraction (pmol) 25th 1.0 26th > 100 27th 0.25 28th > 100 29th 0.26 30th 0,038 31st > 100 32nd > 100 BRL 24682 0.086

It is apparent from previous pharmacological experiments that the compounds of the present invention have 5-HT ₃ antagonist and ACh release accelerating activity and are therefore useful for enhancing gastrointestinal functions such as gastric emptying function and as an emetic and anti-nausea agent.

Thus, the compounds of the present invention have 5-HT ₃ antagonist and ACh release accelerating activity and can be used as medicaments based on such activity.

The acetylcholine release accelerating effect is based on the 5-HT ₄ agonist activity of the compounds of the invention.

The compounds of the present invention are active against various diseases, such as irritable bowel syndrome, reflux esophagitis, gastrointestinal symptoms (such as heartburn, loss of appetite, nausea, vomiting, abdominal pain and abdominal distension) caused by chronic gastritis, gastritis, gastric anticancer drugs and radiation-induced gastrointestinal symptoms and gastrointestinal insufficiency; and restlessness, migraine, amnesic symptoms, dementia in the elderly, Alzheimer's disease and addiction. The compounds of the present invention are particularly useful in balancing 5-HT ₃ antagonism with ACh release accelerating activity and are thus particularly effective in treating gastrointestinal symptoms and gastrointestinal insufficiency.

The compounds of the present invention are less toxic and safer and thus more useful in this sense.

When the compounds of Examples 4 and 43 were administered orally to rats at up to 30 mg / kg for 1 week, no toxicity was observed.

When the above two compounds are administered orally to hunting dogs, no toxicity is observed at doses up to 1.5 mg / kg.

The compounds of the invention may be administered in the form of tablets, powders, granules, capsules, syrups or inhalers for therapeutic or prophylactic uses in the aforementioned disorders. The dosage is highly dependent on the symptoms, the age of the patient, the type of disease, and the dosage for adults is about 0.01 to 1000 mg, preferably 0.1 to 500 mg, particularly 0.1 to 100 mg per day, and may be administered in one or more portions per day.

When the compound of the invention is administered in the form of an injection, the dosage will generally be in the range of 1 to 3000 pg / kg, preferably about 3 to 1000 µg / kg.

The compositions of the invention are prepared using conventional carriers in known manner.

Solid compositions for oral administration according to the invention may be formulated into excipients and optionally excipients, disintegrants, lubricants, colorants and / or flavoring agents, and the resulting mixture formulated into tablets, coated tablets, granules, powders or capsules.

The filler may be lactose, wheat starch, sucrose, glucose, sorbitol, crystalline cellulose and silica, and the binder may be polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, acacia, gum tragacanth, gelatin. , shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin; lubricants include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oil; the coloring agent may be an authorized such material, the flavoring agent may be cocoa powder, mint tea, aroma powder, mint oil, bomeol and cinnamon powder. The tablets and granules may conveniently be coated with sugar, gelatin or the like.

The injectable compositions of the present invention are prepared by adding, as appropriate, pH-adjusting eyes, buffer, stabilizers and / or solubilizing eyes to the active ingredient, and the mixture is formulated for injection by the subcutaneous, intramuscular or intravenous route.

Examples

The following non-limiting examples illustrate the invention.

In the examples, Me is methyl and Ac is acetyl.

The example

Methyl 4- (acetylamino) -5-chloro-2 - {(3-pentin-2-yl) oxy} benzoate Compound A

Triphenylphosphine (146.4 g) was dissolved in tetrahydrofuran (500 mL). To the resulting solution was added diethyl azo carboxylate (97.2 g), 3-pentin-2-ol (33.2 g) and methyl 4- (acetylamino) -5-chlorosalicylate at -65 ° C under nitrogen. (80 g) in tetrahydrofuran (1.4 L) was gradually added dropwise. The reaction mixture was allowed to rise to room temperature and stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and added dropwise with stirring

N-hexane (1.3 L). The precipitated crystalline material is filtered off and the filtrate is concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain 74.3 g of the title compound.

1 H-NMR (400 MHz, CDCl 3): δ ppm:

1.65 (d, J = 5.5 Hz, 3H), 1.82 (d, J = 2.0 Hz, 3H),

2.26 (s, 3H), 3.86 (s, 3H), 4.85-4.94 (m, 1H), 7.72 (broad s, 1H), 7.88 (s, 1H), 8.46 (s, 1H).

Example B

Methyl 4-amino-5-chloro-2 - {(3-pentin-2-yl) oxy} benzoate Compound B

To a suspension of methyl 4- (acetylamino) -5-chloro-2 - {(3-pentin-2-yl) oxy} benzoate (73.3 g) in methanol (700 ml) was added dropwise a solution of sulfuric acid at 0 ° C. (73 mL). The temperature of the reaction mixture was allowed to rise to room temperature. The resulting reaction mixture was stirred overnight at room temperature and then poured into saturated aqueous sodium bicarbonate solution (5 L) gradually. The precipitated crystals were collected by filtration, washed with water and dried to give 66.5 g of the title compound as colorless crystals.

1 H-NMR (400 MHz, CDCl 3): δ ppm:

1.66 (d, J = 6.5 Hz, 3H), 1.81 (d, J = 2.0 Hz, 3H),

3.81 (s, 3H), 4.41 (broad s, 2H), 4.70-4.78 (m,

1H), 6.53 (s, 1H), 7.82 (s, 1H).

Example C

4-Amino-5-chloro-2 - {(3-pentin-2-yl) oxy} benzoic acid Compound C

To a suspension of methyl 4-amino-5-chloro-2 - {(3-pentin-2-yl) oxy} benzoate (56.0 g) in methanol (1.3 L) is added aqueous sodium hydroxide solution ( 5 n, 140 mL). The resulting reaction mixture was stirred at 50 ° C for 6 hours and then at room temperature for 3 days. To the reaction mixture was added water (1 liter) and acidified with 2N hydrochloric acid. The precipitated crystalline material was collected by filtration, washed with water and dried to give 51.5 g of the title compound as colorless crystals.

1 H-NMR (400 MHz, CDCl 3): δ ppm:

1.50 (d, J = 6.5 Hz, 3H), 1.79 (d, J = 2.0 Hz, 3H),

4.81-4.84 (m, 1H), 6.07 (broad s, 2H), 6.53 (s,

1H), 7.56 (s, 1H).

114-116 ° C.

Example D (S) -4-Amino-5-chloro-2 - {(3-pentin-2-yl) oxy} benzoic acid Compound (D) (±) -4-Amino-5-chloro-2- {(3-Pentin-2-yl) oxy} benzoic acid (15.2 g) was dissolved in ethanol (105 mL) and (+) - dehydroabiethylamine (17.1 g) in ethanol (15 mL) was added to the resulting solution at room temperature. ml) in the form of a solution. The resulting reaction mixture was allowed to stand for 2 hours. The precipitated crystalline material was collected by filtration and washed with a small amount of ethanol. The crystalline material thus obtained was dissolved in aqueous sodium hydroxide solution (1N) and extracted with dichloromethane. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with chloroform. The organic phase was dried and concentrated in vacuo to give 4.23 g of white crystals.

The resulting crystalline material was dissolved in ethyl acetate (70 mL) and (S) - (-) - naphthylethylamine (2.67 mL) was added to the resulting solution. The reaction mixture was allowed to stand for 1 hour. The precipitated crystals were collected by filtration and washed with a small amount of ethyl acetate. The crystalline material thus obtained was dissolved in 1N hydrochloric acid and extracted with chloroform. The organic phase was dried and concentrated in vacuo to give 2.23 g of white crystals.

The resulting crystalline material was redissolved in ethyl acetate (45 mL) and (S) - (-) - naphthylethylamine (1.41 mL) was added. The resulting reaction mixture was allowed to stand for 1 hour. The precipitated crystals were collected by filtration and washed with a small amount of ethyl acetate. The crystals thus obtained were dissolved in 1N hydrochloric acid and the solution was extracted with chloroform. The organic phase was dried and concentrated in vacuo to give 1.50 g (99.6%) of the title compound as a white crystalline solid.

Example 1 Endo-4-Amino-5-chloro-N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2 - {(3-pentin-2-yl) - oxy} -benzamide (1)

400 mg 4-amino-5-chloro-2 - {(3-pentin-2-yl) oxy) benzoic acid and 400 mg endo-3-amino-8-methyl-8-azabicyclo [3.2.1] Octane is dissolved in 20 ml of pyridine and 0.38 ml of 5N aqueous sodium hydroxide solution are added at room temperature with stirring. The resulting mixture was stirred for 10 minutes and then 650 mg of 1,3-dicyclohexylcarbodiimide was added. The resulting reaction mixture was stirred at room temperature for 8 hours and water (30 mL) was added. The resulting reaction mixture was filtered to remove insoluble material, and the filtrate was made basic with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (10% methanol / chloroform) to obtain 450 mg of the title compound as a white crystalline solid.

1 H-NMR (400 MHz, d ₆ -DMSO): δ ppm:

1.56-1.65 (m, 5H), 1.75-1.85 (m, 5H), 1.95-2.13 (m, 4H), 2.18 (s, 3H), 3, 00-3.13 (m, 2H),

3.93-4.00 (m, 1H), 5.05-5.13 (m, 1H), 5.89 (broad s, 2H), 6.59 (s, 1H), 7.70 (s) , 1H), 7.87 (d, J = 6.0 Hz, 1H).

Melting point: 173-175 ° C.

Example 2 Endo-4-Amino-5-chloro-N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -3 - {(3-pentin-2-yl) - oxy} benzamide hydrochloride Compound 2

450 mg of endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -3 - {(3-pentin-2-yl) oxy } benzamide10

Dissolve BI salt in 5 ml ethanol, add ethanolic hydrochloric acid and diethyl ether. Collect the precipitated salt by filtration. 320 mg of the title compound are obtained as a pale orange crystalline solid.

1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.60 (d, J = 6.5 Hz, 3H), 1.82 (d, J = 2.0 Hz, 3H),

1.98-2.48 (m, 8H), 2.64 (d, J = 6.0 Hz, 3H),

3.75-3.93 (m, 2H), 3.95-4.05 (m, 1H), 5.05-5.13 (m, 1H), 5.95 (broad s, 2H), δ , 61 (s, 1H), 7.63 (s,

1H), 7.92 (d, J = 5.0 Hz, 1H).

Example 3 (-) - Endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(3-pentin-2) -yl) oxy} benzamide (+) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {( 3-Pentin-2-yl) oxy} benzamide Compound 3

800 mg of the racemic compound of Example 2 were subjected to high performance liquid chromatography (HPLC) on a chiral column (Daicel Chemical Industries Ltd., CHIRALCEL OD) and the mobile phase as a solvent (ethanol: hexane: triethylamine = 20:80). 0, l). 370 mg of (-) isomer and 300 mg of (+) - isomer are obtained.

(-) - isomer

1 H-NMR (400 MHz, CDCl ₃ ): δ ppm:

1.68-1.83 (m, 5H), 1.84 (d, J = 3.0 Hz, 3H),

1.85-1.95 (m, 2H), 2.05-2.15 (m, 2H), 2.20-2.29 (m, 2H), 2.30 (s, 3H), 3.11-. 3.18 (m, 2H),

4.18-4.25 (m, 1H), 4.35 (broad s, 2H), 4.93 (qq,

J = 3.0.7.0 Hz, 1H), 6.46 (s, 1H), 7.98 (d, J = 5.5 Hz,

1H), 8.09 (s, 1H).

(+) - isomer

1 H-NMR (400 MHz, CDCl ₃ ): δ ppm:

1.66-1.79 (m, 5H), 1.84 (d, J = 3.0 Hz, 3H),

1.85-1.94 (m, 2H), 2.06-2.15 (m, 2H), 2.20-2.31 (m, 2H), 2.32 (s, 3H), 3.10-. 3.18 (m, 2H),

4.16-4.24 (m, 1H), 4.93 (qq, J = 3.0, 7.0 Hz, 1H),

6.46 (s, 1H), 7.98 (d, J = 5.5 Hz, 1H), 8.08 (s, 1H).

144-145 ° C.

Example 4 (-) - Endo-4-Amino-5-chloro-N - (- methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(3-pentin-2- yl) oxy} benzamide hydrochloride

1.85 g of (-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(3-pentin-2- Il) oxy} benzamide is dissolved in 9 ml of ethanol and 2.46 ml of 2N hydrochloric acid and 90 ml of water are added. The resulting reaction mixture was freeze-dried to give the title (-) - isomeric hydrochloride (1.99 g).

M / Z (M + H) +: m / z (FAB): 376 (M + + 1)

1 H-NMR (400 MHz, d ₆ -DMSO): δ ppm:

1.62 (d, J = 6.5 Hz, 3H), 1.84 (d, J = 2.0 Hz, 3H),

2.03-2.4 (m, 8H), 2.67 (d, J = 5.0 Hz, 3H),

3.82-3.91 (m, 2H), 4.00-4.05 (m, 1H), 5.10-5.14 (m, 1H), 5.96 (broad s, 2H), δ , 63 (s, 1H), 7.66 (s,

1H), 7.93 (d, J = 5.0 Hz, 1H), 9.92 (s, 1H).

5-19. example

The following compounds were prepared in a similar manner to that described in Example 1.

Example 5 Endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(1-pentin-3-yl) - oxy} benzamide Compound 5

1 H-NMR (400 MHz, d ₆ -DMSO): δ ppm:

1.03 (t, J = 8.0 Hz, 3H), 1.52 (t, J = 12.0 Hz, 2H), 1.68-1.74 (m, 2H), 1.84-2 , 12 (m, 6H), 2.14 (s, 3H), 3.03 (broad s, 2H), 3.93-4.02 (m, 1H), 4.94 (t, J = 4, 0 Hz, 1H), 5.94 (s, 2H), 6.60 (s, 1H), 7.67 (s, 1H), 7.78 (d, J = 6.0 Hz, 1H).

Melting point: 182-184 ° C.

Example 6 Endo-4-Amino-5-chloro-N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2-propargyloxy-benzamide (6) compound

1 H-NMR (400 MHz, d ₆ -DMSO): δ ppm:

1.50-1.70 (m, 2H), 1.75-1.90 (m, 2H), 1.93-2.13 (m, 4H), 2.22 (s, 3H), 3.10-. 3.20 (m, 2H), 3.71 (t, J = 2.0 Hz, 1H), 3.94-4.01 (m, 1H), 4.88 (d, J = 2.0 Hz) , 2H), 5.99 (s broad, 2H), 6.52 (s, 1H),

7.67 (s, 1H), 7.99 (d, J = 5.0 Hz, 1H).

Example 7 Endo-4-Amino-2- (2-butyn-1-yloxy) -5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide Compound 7

1 H-NMR (400 MHz, d ₆ -DMSO): δ ppm:

1.51-1.58 (m, 2H), 1.75-1.83 (m, 2H), 1.84 (t, J = 2.5 Hz, 3H), 1.95-2.10 (m, 4H), 2.15 (s, 3H), 3.00-3.03 (m, 2H), 3.96-3.98 (m, 1H), 4.82 (q, J = 2.5 Hz). , 2H), 5.97 (s, 2H), 6.50 (s, 1H), 7.69 (s, 1H), 8.06 (d, J = 7.0 Hz, 1H).

Mp 188-191 ° C.

Example 8 Endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2- (3-pentin-1-yloxy) Benzamide Compound (8)

1 H-NMR (400 MHz, d ₆ -DMSO): δ ppm: 1.58-1.68 (m, 2H), 1.71 (t, J = 2.5 Hz, 3H),

1.73-1.80 (m, 2H), 1.90-2.10 (m, 4H), 2.66 (narrow q, J = 6.5, 2.5 Hz, 2H), 3.00 -3.10 (m, 2H), 3.95-3.97 (m, 1H), 4.12 (t, J = 6.5 Hz, 2H), 5.90 (s, 2H), 6, 49 (s, 1H), 7.70 (s, 1H), 7.90 (d, J = 6.5 Hz, 1H).

Example 9 Endo-4-Amino-2 - {(3-butyn-2-yl) oxy} -5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide Compound 9

1 H-NMR (400 MHz, d ₆ -DMSO): δ ppm:

1.52-1.60 (m, 2H), 1.64 (d, J = 6.5 Hz, 3H), 1.71-1.78 (m, 2H), 1.95-2.08 (m, 4H), 2.13 (s, 3H), 2.97-3.03 (m, 2H), 3.70 (d, J = 3.0 Hz, 1H),

3.93-3.99 (m, 1H), 5.14 (dq, J = 3.0, 6.5 Hz, 1H),

HU 221 301 Bl

5.97 (s broad, 2H), 6.59 (s, 1H), 7.68 (s, 1H), 7.81 (d, J = 6.5 Hz, 1H).

Example 10 Endo-4-Amino-5-chloro-2 - {(4-heptin-3-yl) oxy} -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide Compound 10 • 1 H-NMR (400 MHz, CDCl ₃ ): δ ppm:

1.10 (t, J = 8.0 Hz, 3H), 1.12 (t, J = 8.0 Hz, 3H), 1.71-2.31 (m, 12H), 2.32 (s) , 3H), 3.16 (bs, 2H), 4.20 (dd, J = 4.0, 11.0 Hz, 1H), 4.35 (bs, 2H), 4.73-4, 78 (m, 1H), 6.43 (s, 1H), 7.98 (broad s, 1H), 8.09 (s, 1H).

Example 11 Endo-4-Amino-5-chloro-2 - {(4-heptin-2-yl) oxy} -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide Compound 11 • 1 H-NMR (400 MHz, CDCl ₃ ): δ ppm:

1.10 (t, J = 7.5 Hz, 3H), 1.52 (d, J = 6.0 Hz, 3H),

1.74-1.92 (m, 6H), 2.08-2.18 (m, 3H), 2.26-2.34 (m, 1H), 2.33 (s, 3H), 2, 52 (type A ₂ BX, J = 2.5, 2.5, 16.0 Hz, 1H), 3.20 (broad s, 2H), 4.16-4.24 (m, 1H), 4, 33 (bs, 2H), 4.52-4.63 (m, 1H), 6.32 (s, 1H), 7.96 (bs, 1H), 8.10 (s, 1H).

Example 12 Endo-4-Amino-5-chloro-2 - {(2-hexin-4-yl) oxy} -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide Compound 12 • 1 H-NMR (400 MHz, cU-DMSO): δ ppm:

1.02 (t, J = 7.5 Hz, 3H), 1.50-1.63 (m, 2H), 1.70-1.80 (m, 2H), 1.83 (d, J = 2.0 Hz, 3H),

1.85-2.13 (m, 6H), 2.16 (s, 3H), 3.00-3.10 (m, 2H), 3.91-4.00 (m, 1H), 4, 88-4.94 (m, 1H), 5.92 (bs, 2H), 6.58 (s, 1H), 7.68 (s, 1H), 7.85 (d, J = 6.0). Hz, 1H).

Example 13 Endo-4-Amino-5-chloro-2 - {(3-hexin-2-yl) oxy} -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide Compound 13 • 1 H-NMR (400 MHz, t-DMSO + CDCl 3 δ ppm: 1.02 (t, J = 7.5 Hz, 3H), 1.55-1.65 (m, 5H), 1.73-1.85 (m, 2H), 1.95-2.10 (m, 4H), 2.15-2.23 (m, 5H), 3.00-3.13 ( m, 2H), 3.93-4.00 (m, 1H), 5.12 (qt, J = 6.5, 2.0 Hz, 1H), 5.93 (broad s, 2H),

6.59 (s, 1H), 7.69 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H) Melting point: 144-145 ° C.

Example 14 Endo-4-Amino-5-chloro-2 - {(1-hexin-3-yl) oxy} -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide Compound 14 • 1 H-NMR (400 MHz, d ₆ -DMSO): δ ppm:

0.93 (t, J = 7.5 Hz, 3H), 1.40-1.60 (m, 4H); 1.62-1.78 (m, 2H), 1.80-2.22 (m, 6H), 2.15 (s, 3H), 3.00 (broad s, 2H), 3.70 (s) , 1H), 3.90-4.00 (m, 1H), 4.98 (t, J = 4.0 Hz, 1H), 5.94 (br s, 2H),

6.60 (s, 1H), 7.69 (s, 1H), 7.76 (d, J = 6.0 Hz, 1H).

Example 15 Endo-4-Amino-5-chloro-2- (2-fluoroethoxy) -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -benzamide (15) compound • 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.50-1.60 (m, 2H), 1.62-1.75 (m, 2H), 1.90-2.18 (m, 4H), 2.13 (s, 3H), 2, 98-3.03 (m, 2H), 3.95-4.00 (m, 1H), 4.25-4.28 (m, 1H), 4.32-4.35 (m, 1H), 4.75-4.77 (m, 1H), 4.88-4.90 (m, 1H), 5.92 (broad s, 2H), 6.55 (s, 1H), 7.68 (s) , 1H), 7.77 (d, J = 7.0 Hz, 1H).

Example 16 Endo-4-Amino-5-chloro-2- (3-cyanopropoxy) -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) benzamide (16 • 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.52-1.59 (m, 2H), 1.65-1.74 (m, 2H), 1.95-2.15 (m, 6H), 2.13 (s, 3H), 2.66 ( t, J = 7.0 Hz, 2H), 2.97-3.02 (m, 2H), 3.94-3.99 (m, 1H), 4.14 (t, J = 6.0 Hz) , 2H), 5.90 (bs, 2H), 6.50 (s, 1H), 7.66 (s, 1H), 7.80 (d, J = 7.0 Hz, 1H).

Reference Example 17 Endo-4-Amino-5-chloro-2- (1-cyclopentyl-ethoxy) -N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -benzamide (17) • 1 H-NMR (400 MHz, (1 H-DMSO) δ ppm)

1.18-1.35 (m, 5H), 1.43-1.65 (m, 6H), 1.66-1.83 (m, 4H), 1.93-2.23 (m, 8H) ), 3.01-3.13 (m, 2H),

3.93-4.00 (m, 1H), 4.22-4.31 (m, 1H), 5.84 (s, 2H), 6.56 (s, 1H), 7.70 (s, 1H), 7.96 (d, J = 5.5 Hz, 1H).

Reference Example 18 Endo-4-Amino-5-chloro-N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2- (tetrahydro-4H-pyran-4-oxy) Benzamide Compound 18 • 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.53-1.80 (m, 6H), 1.93-2.13 (m, 6H), 2.17 (s, 3H), 3.00-3.13 (m, 2H), 3.38-. 3.48 (m, 2H), 3.88-3.98 (m, 3H), 4.51-4.61 (m, 1H), 5.85 (br s, 2H), 6.62 (s , 1H), 7.68 (s, 1H), 7.85 (d, J = 6.0 Hz, 1H).

Example 19 Endo-4-Amino-5-chloro-2- (4-methoxy-cyclohexyloxy) -N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -benzamide ( Compound 19 • 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.20-1.35 (m, 1H), 1.43-1.68 (m, 4H), 1.69-1.81 (m, 3H), 1.82-1.91 (m, 1H) ), 1.95-2.25 (m, 10H), 3.23 (s, 3H), 3.26-3.36 (m, 2H), 3.39-3.50 (m, 1H), 3.91-4.00 (m, 1H), 4.30-4.43 (m, 1H), 5.83 (broad s, 2H), 6.57 (s, 1H), 7.68 (s). , 1H), 7.85 (d, J = 5.0 Hz, 1H).

20-34. example

The following compounds were prepared in a similar manner to that described in Example 2.

HU 221 301 Bl

Example 20 Endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(1-pentin-3-yl) - oxy} benzamide hydrochloride Compound 20 1 H-NMR (400MHz, d 6 -DMSO) δ ppm:

1.02 (t, J = 8.0 Hz, 3H), 1.82-2.12 (m, 6H),

2.21-2.24 (m, 2H), 2.40-2.44 (m, 2H), 2.62 (d, J = 6.0 Hz, 3H), 3.72 (s, 2H) , 3.82 (broad s, 2H),

3.93-4.03 (m, 1H), 4.93 (t, J = 4.0 Hz, 1H), 6.62 (s, 1H), 7.60 (s, 1H), 7.86 (d, J = 5.0 Hz, 1H).

MS m / z (FAB): 376 (M + +1).

Example 21 Endo-4-amino-5-chloro- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2-propargyloxy-benzamide hydrochloride (21) Compound 1 H-NMR (400 MHz, φ, -DMSO) δ ppm:

1.90-2.10 (m, 2H), 2.11-2.30 (m, 4H), 2.41-2.53 (m, 2H), 2.63 (s, 3H), 3, 72 (t, J = 2.0 Hz, 1H), 3.78-3.85 (m, 2H), 3.94-4.03 (m, 1H), 4.86 (d, J = 2, 0 Hz, 1H), 6.01 (s broad, 2H), 6.53 (s, 1H),

7.62 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H).

Melting point: 242-245 ° C.

Example 22 Endo-4-Amino-2- (2-butyn-1-yloxy) -5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide hydrochloride Compound 22 1 H-NMR (400 MHz, d 6 -DMSO) δ ppm:

1.86 (bs, 3H), 2.00-2.06 (m, 2H), 2.15-2.31 (m, 4H), 2.36-2.45 (m, 2H), 2 , 65 (s, 3H),

3.80-3.88 (m, 2H), 3.96-4.04 (m, 1H), 4.8 (br s, 2H), 6.00 (br s, 2H), 6.50 (s, 1H), 7.63 (s, 1H), 8.05 (d, J = 7.0 Hz, 1H).

MS m / z (FAB): 362 (M ⁺ +1).

Mp 263-265 ° C,

Example 23 Endo-4-Amino-5-chloro-N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2- (3-pentin-1-yloxy) benzamide hydrochloride Compound 23 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.74 (t, 2.5 Hz, 3H), 2.06-2.15 (m, 2H), 2.20-2.30 (m, 4H), 2.38-2.46 (m, 2H), 2.64-2.73 (m, 5H),

3.80-3.93 (m, 2H), 3.95-4.03 (m, 1H), 4.10 (t, J = 6.5 Hz, 2H), 6.51 (s, 1H), δ , 65 (s, 1H), 7.93 (d, J = 7.0 Hz, 1H), MS m / z (FAB): 376 (M + +1).

Example 24 Endo-4-Amino-2 - {(3-butyn-2-yl) oxy} -5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide Hydrochloride Compound 24 1 H-NMR (400 MHz,? VDMSO) δ ppm:

1.63 (d, J = 6.5 Hz, 3H), 1.97-2.30 (m, 6H), 2.46-2.57 (m, H), 2.61 (d, J = 5, 0 Hz, 3H), 3.71 (d,

J = 3.0 Hz, 1H), 3.78-3.85 (m, 2H), 3.95-4.00 (m, 1H), 4.68 (br s, 2H), 5.12 ( dq, J == 3.0, 6.5 Hz, 1H), 6.62 (s, 1H), 7.61 (s, 1H), 7.88 (d, J = 6.0 Hz, 1H) , 10.68 (br s, 1H). MS m / z (FAB): 362 (M + +1)

Melting point: 154-158 ° C.

Example 25 Endo-4-Amino-5-chloro-2 - {(4-heptin-3-yl) oxy} -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide hydrochloride Compound 25 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm: 0.98-1.08 (m, 6H), 1.78-2.30 (m, 10H) .

2.50-2.58 (m, 2H), 2.63 (d, J = 5.0 Hz, 3H), 3.83 (broad s, 2H), 3.93-4.00 (m, 1H ), 4.90-4.96 (m, 1H), 6.63 (s, 1H), 7.64 (s, 1H), 7.94 (broad s, 1H).

Example 26 Endo-4-Amino-5-chloro-2 - {(4-heptin-2-yl) oxy} -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide hydrochloride Compound 26 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

0.99 (t, J = 7.5 Hz, 3H), 1.40 (d, J = 4.0 Hz, 3H), 2.00-2.16 (m, 6H), 2.18-2 , 30 (m, 2H), 2.40-2.54 (m, 2H), 2.57-2.66 (m, 2H), 2.63 (d, J = 5.0 Hz, 3H), 3.84 (bs, 2H), 3.94-3.99 (m, 1H); 4.53-4.62 (m, 1H), 6.56 (s, 1H), 7.66 (s, 1H), 7.92 (d, J = 5.0 Hz, 1H), 10.40 (broad s, 1H).

Example 27 Endo-4-Amino-5-chloro-2 - {(2-hexin-4-yl) oxy} -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) benzamide hydrochloride Compound 27 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.01 (t, J = 7.5 Hz, 3H), 1.84 (d, J = 2.0 Hz, 3H),

1.85-2.10 (m, 6H), 2.23-2.33 (m, 2H), 2.39-2.50 (m, 2H), 2.65 (d, J = 6.0 Hz, 3H), 3.81-3.88 (m, 2H), 3.96-4.04 (m, 1H), 4.88-4.95 (m, 1H), 5.95 (broad s) , 2H), 6.61 (s, 1H), 7.63 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H).

137-141 ° C.

Example 28 Endo-4-Amino-5-chloro-2 - {(3-hexin-2-yl) oxy} -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide hydrochloride Compound 28 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.04 (t, J = 7.5 Hz, 3H), 1.60 (d, J = 6.5 Hz, 3H), 1.98-2.33 (m, 8H), 2.38-2 , 58 (m, 2H), 2.65 (d, J = 5.0 Hz, 3H), 3.80-3.90 (m, 2H), 3.96-4.04 (m, 1H), 5.11 (qt, J = 6.5, 2.0 Hz, 1H), 5.98 (br s, 2H), 6.61 (s, 1H), 7.64 (s, 1H), 7, 94 (d, J = 5.0 Hz, 1H).

134-136 ° C.

HU 221 301 Β1

Example 29 Endo-4-Amino-5-chloro-2 - {(1-hexin-3-yl) oxy} -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) benzamide hydrochloride Compound 29 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

0.93 (t, J = 7.5 Hz, 3H), 1.42-1.55 (m, 2H), 1.67-2.15 (m, 6H), 2.20-2.30 ( m, 2H), 2.40-2.50 (m, 2H), 2.63 (d, J = 5.0 Hz, 3H), 3.70 (s, 1H), 3.78-3.85 (m, 2H), 3.95-4.02 (m, 1H), 4.96 (t, J = 4.0 Hz, 1H), 5.20 (broad s, 2H), 6.62 (s) , 1H),

7.60 (s, 1H), 7.82 (d, J = 6.0 Hz, 1H).

MS m / z (FAB): 390 (M + + 1)

138-140 ° C.

Example 30 Endo-4-Amino-5-chloro-2- (2-fluoroethoxy) -N- (8-methyl8-azabicyclo [3.2.1] oct-3-yl) -benzamide hydrochloride 1 H-NMR (400 MHz, d (-DMSO) δ ppm:

1.94-2.23 (m, 6H), 2.40-2.52 (m, 2H), 2.62 (broad s, 3H), 3.72-3.85 (m, 2H), 3 , 94-4.04 (m, 1H), 4.26-4.29 (m, 1H), 4.33-4.37 (m, 1H), 4.74-4.78 (m, 1H) , 4.87-4.90 (m, 1H), 6.04 (s broad, 2H), 6.51 (s, 1H), 7.67 (s, 1H), 7.95 (d, J = 7.0 Hz, 1H). Mp 260-262 ° C.

Example 31 Endo-4-Amino-5-chloro-2- (3-cyanopropoxy) -N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -benzamide hydrochloride Compound of Formula 31 1 H-NMR (400 MHz, dg-DMSO) δ ppm:

2.03-2.13 (m, 6H), 2.22-2.27 (m, 2H), 2.38-2.46 (m, 2H), 2.64 (d, J = 5.4) Hz, 3H), 2.68 (t, J = 7.5 Hz, 2H), 3.82 (m, 2H), 3.94-4.00 (m, 1H), 4.12 (t, J = 6.8 Hz, 2H), 5.93 (broad s, 2H), 6.52 (s, 1H), 7.56 (s, 1H), 7.88 (d, J = 4.8 Hz, 1 H), 10.14 (broad s, 1H).

MS m / z (FAB): 377 (M + +1).

Melting point: 130-132 ° C.

Reference Example 32 Endo-4-Amino-5-chloro-2- (1-cyclopentyl-ethoxy) -N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -benzamide hydrochloride (32 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.16-1.33 (m, H), 1.43-1.65 (m, 4H), 1.66-1.80 (m, 2H), 1.88-2.08 (m, 4H) ), 2.10-2.18 (m, 1H),

2.20-2.35 (m, 2H), 2.38-2.65 (m, 5H), 3.79-3.86 (m, 2H), 3.95-4.01 (m, 1H) ), 4.23-4.31 (m, 1H), 6.59 (s, 1H), 7.65 (s, 1H), 7.98 (d, J = 5.0 Hz, 1H), 10 , 55 (broad s, 1H).

Melting point: 154-156 ° C.

Reference Example 33 Endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2- (tetrahydro-4H-pyran-4-oxy) benzamide hydrochloride Compound 33 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.55-1.68 (m, 2H), 2.01-2.12 (m, 6H), 2.23-2.30 (m, 2H), 2.35-2.45 (m, 2H) ), 2.64 (d, J = 5.0 Hz,

3H), 3.38-3.48 (m, 2H), 3.80-3.87 (m, 2H),

3.89-4.00 (m, 3H), 4.50-4.59 (m, 1H), 5.88 (broad s, 2H), 6.63 (s, 1H), 7.61 (s). , 1H), 7.90 (d, J = 6.0 Hz, 1H).

Mp 226-228 ° C.

Example 34 Endo-4-Amino-5-chloro-2- (4-methoxy-cyclohexyloxy) -N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -benzamide hydrochloride Compound 34 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.20-1.30 (m, 1H), 1.38-1.58 (m, 2H), 1.60-1.75 (m, 1H), 1.80-1.90 (m, 1H), 1.95-2.15 (m, 7H),

2.20-2.30 (m, 2H), 2.35-2.45 (m, 2H), 2.64 (s,

3H), 3.14-3.20 (m, 1H), 3.23 (s, H), 3.80-3.88 (m,

2H), 3.93-4.00 (m, 1H), 4.28-4.40 (m, 1H), 5.88 (broad s, 2H), 6.58 (s, 1H), 7, 61 (s, 1H), 7.91 (d,

J = 5.0 Hz, 1H).

Example 35 (-) - Endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(1-pentin-3) -yl) oxybenzamide (+) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(1-pentine) -3-yl) oxy} benzamide Compound 35

The title compound was prepared as described in Example 3.

(-) - isomer

Melting point: 179-182 ° C.

(+) - isomer

Melting point: 183-184 ° C.

36-38. example

The following compounds were prepared as described in Example 4.

Example 36 (+) - Endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - [(3-pentin-2) -yl) oxy} benzamide hydrochloride Compound 36 1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.60 (d, J = 6.5 Hz, 3H), 1.82 (d, J = 2.0 Hz, 3H),

1.95-2.09 (m, 2H), 2.10-2.17 (m, 2H), 2.23-2.32 (m, 2H), 2.33-2.45 (m, 2H) ), 2.65 (d, J = 5.0 Hz,

3H), 3.82-3.86 (m, 2H), 3.98-4.03 (m, 1H),

5.06-5.14 (m, 1H), 5.98 (broad s, 2H), 6.60 (s,

1H), 7.63 (s, 1H), 7.92 (d, J = 5.0 Hz, 1H).

MS m / z (FAB): 376 (M + 1) [a] ^{2 5} D = 97.25 ° (c = 09, MeOH)

Example 37 (-) - Endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(1-pentin-3) yl) oxy} benzamide hydrochloride

1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.02 (t, J = 8.0 Hz, 3H), 1.82-2.12 (m, 6H),

2.21-2.24 (m, 2H), 2.40-2.44 (m, 2H), 2.62 (d,

J = 6.0 Hz, 3H), 3.72 (s, 2H), 3.82 (s broad, 2H),

3.93-4.03 (m, 1H), 4.93 (t, J = 4.0 Hz, 1H); 6.62 (s,

1H), 7.60 (s, 1H), 7.86 (d, J = 5.0 Hz, 1H).

MS m / z (FAB): 376 (M ⁺ 1) [a] ^{2 5} D = -74.55 ° (c = 12, MeOH)

144-147 ° C.

Example 38 (+) - Endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(1-pentin-3) -yl) oxy} benzamide hydrochloride Compound 38 1 H-NMR (400 MHz, de-DMSO) δ ppm:

1.02 (t, J = 8.0 Hz, 3H), 1.82-2.12 (m, 6H),

2.21-2.24 (m, 2H); 2.40-2.44 (m, 2H), 2.62 (d,

J = 6.0 Hz, 3H), 3.72 (s, 2H), 3.82 (s broad, 2H),

3.93-4.03 (m, 1H), 4.93 (t, J = 4.0 Hz, 1H), 6.62 (s,

1H), 7.60 (s, 1H), 7.86 (d, J = 5.0 Hz, 1H).

MS m / z (FAB): 376 (M ⁺ + 1) [α] 25 D = 76.36 ° (c = 1.10, MeOH)

146-148 ° C.

Example 39 Endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - ((4-pentin-2-yl) - oxy} benzamide (39) g 4-amino-5-chloro-2 - {(4-pentin-2-yl) oxy} benzoic acid and 10 g endo-3-amino-8-methyl-8- Azabicyclo [3.2.1] octane is dissolved in 50 ml of pyridine, 5N aqueous sodium hydroxide solution and 16.1 g of dicyclohexylcarbodiimide are added, and the resulting mixture is stirred at room temperature overnight and then added with water. The precipitated insoluble material was filtered off and the filtrate was made basic with 5N aqueous sodium hydroxide solution and extracted with chloroform, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. (chloroform) to give 10.7 g of the title compound as colorless crystals.

1 H-NMR (400 MHz, CDCl ₃ ): δ ppm:

1.65 (d, J = 6.0 Hz, 3H), 1.74-1.88 (m, 4H),

2.01-2.13 (m, 3H), 2.21-2.30 (m, 2H), 2.30 (s,

3H), 2.58 (type A ₂ BBX, J = 3.0, 7.0, 17.0 Hz, 1H),

2.68 (type A ₂ BBX, J = 3.0, 5.0, 17.0 Hz, 1H),

3.13-3.19 (m, 2H), 4.18-4.23 (m, 1H), 4.31-4.38 (bs, 2H), 4.60-4.69 (m, 1H), 6.32 (s, 1H),

7.89 (d, J = 3.0 Hz, 1H), 8.10 (s, 1H).

M.p. 208-209 ° C.

Example 40 Endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(4-pentin-2-yl) - oxy} benzamide hydrochloride 40

130 mg endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(4-pentin-2-yl) oxy } benzamide is dissolved in 2 ml of ethanol. The resulting solution was made basic by the addition of a 20% hydrochloric acid / ethanol solution under ice-cooling, and diethyl ether was added. The precipitated crystalline material was collected by filtration and dried to give 140 mg of the title compound as colorless crystals.

1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.41 (d, J = 6.0 Hz, 3H), 2.03-2.14 (m, 4H),

2.21-2.29 (m, 2H), 2.40-2.53 (m, 2H), 2.6-2.68 (m, 5H), 3.01 (t, J = 33.0) Hz, 1H), 3.80-3.85 (m,

2H), 3.98-4.00 (m, 1H), 4.60-4.66 (m, 1H), 6.57 (s, 1H), 7.67 (s, 1H), 7.86 (d, J = 3.0 Hz, 1H).

Example 41 (+) - Endo-4-Amino-5-chloro- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(4-pentin-2-yl) ) oxy} benzamide (-) - endo-4-amino-5-chloro- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(4-pentine) 2-yl) oxy} benzamide Compound 41

The racemic mixture (1.65 g) was subjected to high performance liquid chromatography on a chiral column (Daicel Chemical Industries, Ltd.; CHIRALCEL OD) as the mobile phase solvent (ethanol / hexane / triethylamine = 20: 80: 0.1). 480 mg of (+) isomer and 450 mg of (-) isomer are obtained.

(+) - Isomer 1 H-NMR (400 MHz, CDCl ₃ ): δ ppm:

1.54 (d, J = 6.0 Hz, 3H), 1.71-1.88 (m, 4H),

2.01-2.13 (m, 3H), 2.21-2.30 (m, 2H), 2.30 (s,

3H), 2.58 (type A ₂ BBX, J = 3.0, 7.0, 17.0 Hz, 1H),

2.68 (type A ₂ BBX, J = 3.0, 5.0, 17.0 Hz, 1H),

3.13-3.19 (m, 2H), 4.18-4.23 (m, 1H), 4.35 (broad s, 2H), 4.64 (narrow q, J = 6.0, 6 , 0 Hz, 1H), 6.32 (s, 1H), 7.89 (d, J = 5.5 Hz, 1H), 8.10 (s, 1H).

(-) - isomer:

1 H-NMR (400 MHz, CDCl ₃ ): δ ppm:

1.54 (d, J = 6.0 Hz, 3H), 1.71-1.88 (m, 4H),

2.05-2.15 (m, 2H), 2.20-2.30 (m, 2H), 2.30 (s,

3H), 2.58 (A ₂ BBX type J = 3.0, 7.0, 17.0 Hz, 1H),

2.68 (type A ₂ BBX, J = 3.0, 5.0, 17.0 Hz, 1H),

3.13-3.19 (m, 2H), 4.15-4.24 (m, 1H), 4.33 (broad s, 2H), 4.64 (narrow q, J = 6.0, 6 , 0 Hz, 1H), 6.32 (s, 1H), 7.89 (d, J = 5.5 Hz, 1H), 8.11 (s, 1H).

Example 42 (+) - Endo-4-Amino-5-chloro-N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2 - {(4-pentin-2) -yl) oxy} benzamide hydrochloride

309 mg (+) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(3-pentin-2-yl) oxy} benzamide is dissolved in 1.5 ml of ethanol, then 0.411 ml of 2N hydrochloric acid solution and 15 ml of water are added. The resulting reaction mixture was freeze-dried to give (+) - isomeric hydrochloride (333 mg).

1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.44 (d, J = 6.5 Hz, 3H), 2.07-2.17 (m, 4H),

HU 221 301 Β1

2.26-2.37 (m, 2H), 2.38-2.43 (m, 2H), 2.65-2.71 (m, 5H), 3.00 (t, J = 2.5 Hz, 1H), 3.82-3.93 (m,

2H), 4.01-4.05 (m, 1H), 4.65 (narrow q, J = 6.0,

6.0 Hz, 1H), 5.91 (broad s, 2H), 6.59 (s, 1H), 7.69 (s, 1H), 7.88 (d, J = 5.0 Hz, 1H) ), 9.87 (s, 1H).

MS m / z (FAB): 376 (M + +1).

Example 43 (-) - Endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(4-pentin-2) -yl) oxy} benzamide hydrochloride

The title compound was prepared as described in Example 42.

1 H-NMR (400 MHz, dg-DMSO) δ ppm:

1.42 (d, J = 6.0 Hz, 3H), 2.04-2.13 (m, 4H),

2.23-2.27 (m, 2H), 2.35-2.43 (m, 2H), 2.62-2.67 (m, 5H), 3.01 (t, J = 3.0) Hz, 1H), 3.80-3.84 (m,

2H), 3.96-4.00 (m, 1H), 4.64 (narrow q, J = 6.0,

6.0 Hz, 1H), 6.57 (s, 1H), 7.66 (s, 1H), 7.87 (d,

J = 5.0 Hz, 1H).

MS m / z (FAB): 376 (M + 1) [a] ^{2 5} D = -8.88 ° (c = 07, MeOH)

Example 44 Endo-4-Acetylamino-2- (3-butyn-1-yloxy) -5-chloro-N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) ) Benzamide (44)

Dissolve 260 mg of 4-acetylamino-2- (3-butyn-1-yloxy) -5-chlorobenzoic acid and 216 mg of endo-3-amino-8-methyl-8-azabicyclo [3.2.1] octane. 5 ml of pyridine and 0.2 ml of 5N aqueous sodium hydroxide solution and 300 mg of 1,3-dicyclohexylcarbodiimide are added. The resulting reaction mixture was stirred at room temperature overnight and then water was added. The insoluble precipitate was filtered off and the filtrate was made basic with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (10% methanol / chloroform) to give 130 mg of the title compound as colorless crystals.

1 H-NMR (400 MHz, CDCl ₃ ): δ ppm:

1.85-1.93 (m, 2H), 2.06 (t, J = 3.0 Hz, 1H),

2.13-2.18 (m, 2H), 2.27 (s, 3H), 2.30-2.38 (m,

4H), 2.78 (dt, J = 3.0, 7.0 Hz, 2H), 3.20-3.28 (m,

4H), 4.29-4.26 (m, 1H), 4.35 (t, J = 7.0 Hz, 2H),

7.75-7.78 (m, 1H), 8.05-8.09 (m, 1H), 8.23 (s,

1H), 8.33 (s, 1H).

Example 45 Endo-4-Amino-2- (3-butyn-1-yloxy) -5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide Compound 45

130 mg of endo-4-acetylamino-2- (3-butyn-1-yloxy) -5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) - Benzamide is dissolved in 5 ml of methanol and then a solution of 200 mg of sodium hydroxide in 1 ml of water is added. The resulting reaction mixture was stirred overnight at room temperature. The precipitated crystalline material was collected by filtration, washed with water and dried to give 120 mg of the title compound as colorless crystals.

1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.58-1.64 (m, 2H), 1.70-1.75 (m, 2H), 1.94-2.09 (m, 4H), 2.12 (s, 3H), 2.72 ( dt, J = 3.0, 7.0 Hz, 2H),

2.96-3.02 (m, 3H), 3.27-3.32 (m, 2H), 3.92-3.96 (m, 1H), 4.17 (t, J = 7.0 Hz), 2H), 5.88-5.92 (m,

2H), 6.50 (s, 1H), 7.70 (s, 1H), 7.88 (d, J = 7.0 Hz,

1H).

Example 46 endo-4-amino-2- (3-butyn-1-yloxy) -5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) Benzamide hydrochloride 46 mg endo-3-amino-2- (3-butyn-1-yloxy) -5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] Oct-3-yl) benzamide was dissolved in a mixture of 1 ml of ethanol and 7 ml of water, and 28 μΐ of 2N aqueous hydrochloric acid was added. The resulting reaction mixture was freeze-dried to give 20 mg of the title compound as colorless crystals.

1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

2.06-2.15 (m, 4H), 2.23-2.30 (m, 2H), 2.31-2.40 (m, 2H), 2.65 (s, 3H), 2, 69 (dt, J = 3.0, 7.0 Hz, 2H),

3.01 (t, J = 3.0 Hz, 1H), 3.81-3.86 (m, 2H),

3.96-4.01 (m, 1H), 4.15 (t, J = 7.0Hz, 2H), 6.51 (s,

1H), 7.65 (s, 1H), 7.91 (d, J = 7.0 Hz, 1H).

MS m / z (FAB): 362 (M + +1).

Mp 226-229 ° C.

Example 47 (S) -endo-4-Amino-5-chloro-N- (8,8-dimethyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(3-pentine) -2-yl) oxy} benzamide iodide Compound 47

300 mg of (S) - (-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(3-pentine) 2-yl) oxy} benzamide is dissolved in 2 ml of ethanol and then 0.1 ml of methyl iodide is added at room temperature. The resulting solution was stirred for 4 hours, the precipitated crystals were collected by filtration, washed twice with a small amount of cold ethanol and dried to give the title compound as white crystals (257 mg).

1 H-NMR (400 MHz, d ₆ -DMSO) δ ppm:

1.59-1.60 (d, 3H), 1.82-1.83 (d, 3H), 1.90-1.96 (m, 2H), 2.16-2.20 (d, 2H), 2.38-2.42 (m, 2H),

2.50-2.59 (m, 2H), 3.01 (s, 3H), 3.12 (s, 3H), 3.84 (broad s, 2H), 4.10-4.16 (dd) , 1H), 5.03-5.11 (m,

1H), 5.99 (s, 2H), 6.60 (s, 1H), 7.62 (s, 1H),

7.92-7.95 (d, 1H).

MS m / z (FAB): 390 (M ⁺ + 1)

195 ° C (dec.).

Example 48 (S) -endo-4-Amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -23 - {(3-pentin-2) yl) oxy} benzamide 8-oxide

EN 221 301 Β1 Compound 48

1.13 g of (S) -endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(3-pentin-2- Il) oxy} benzamide was dissolved in dichloromethane (50 mL) and m-chloroperbenzoic acid (0.81 g) was added to the resulting solution under ice-cooling. The resulting solution was stirred for half an hour. After completion of the reaction, the resulting reaction mixture was washed with saturated aqueous sodium bicarbonate solution and saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was treated with diisopropyl ether to give 0.40 g of the title compound.

1 H-NMR (400 MHz, CDCl ₃ ): δ ppm:

1.65, 1.67 (2xd, J = 6.5Hz, 3H), 1.83, 1.84 (2xd,

J = 1.6 Hz, 3H), 1.90-2.40 (m, 6H), 2.47-2.57 (m,

1H), 2.79-2.86 (m, 1H), 3.27, 3.30 (sx2, 3H), 3.43,

3.66 (2xm, 2H), 4.30 (m, 1H), 4.41, 4.45 (2xbr.s,

2H), 4.88 (m, 1H), 6.42, 6.43 (sx2, 1H), 8.08, 8.10 (2xs, 1H), 8.00, 8.14 (2xbrd, J = 5.5 Hz, 1H).

MS m / z (FAB): 392 (M + +1)

Example 49 (S) -exo-4-Amino-5-chloro-N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2 - {(3-pentin-2) -yl) oxy} benzamide Compound 49

The title compound is prepared from exo-3-aminopropane and (S) -4-amino-5-chloro-2 - {(3-pentin-2-yl) oxy} benzoic acid as described in Example 1.

1 H-NMR (400 MHz, CDCl ₃ ): δ ppm:

1.68 (d, J = 6.5 Hz, 3H), 1.83 (d, J = 2.0 Hz, 3H),

1.73-1.88 (m, 4H), 1.92-2.02 (m, 2H), 2.05-2.14 (m, 2H), 2.38 (s, 3H), 3, 32 (m, 2H), 4.32 (m, 1H),

4.42 (bs, 2H), 4.75-4.83 (m, 1H), 6.48 (s,

1H), 7.64 (br d, J = 5.0 Hz, 1H), 8.01 (s, 1H).

MS m / z (FAB): 376 (M ⁺ + 1)

Example 50 (S) -exo-4-Amino-5-chloro-N- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2 - {(3-pentin-2) -yl) oxy} benzamide id-h idro chloride Compound 50

The title compound was prepared as described in Example 2.

1 H-NMR (400 MHz, d 6 -DMSO) δ ppm:

1.63 (d, J = 6.5 Hz, 3H), 1.81 (d, J = 1.5 Hz, 3H),

1.88-2.25 (m, 8H), 2.61 (d, J = 6.0 Hz, 3H), 3.85 (m, 2H), 4.21 (m, 1H), 4.98 (m, 1H), 6.59 (s, 1H),

7.64 (d, J = 5.5 Hz, 1H), 7.65 (s, 1H), 10.94 (broad s, 1H).

MS m / z (FAB): 376 (M ⁺ +1)

Claims (18)

PATENT CLAIMS An aminobenzoic acid derivative of the formula (I), (1-2) and (1-3) and pharmaceutically acceptable salts thereof, wherein: R * is C 3 -C 8 alkynyl, cyano-C 1 -C 5 alkyl, C 1 -C 5 alkyl substituted by halogen, or Substituted with C 1-5 alkoxy C3-C8 cycloalkyl, R ² is amino or (C 2 -C 5 alkanoyl) amino; R ³ is a halogen atom of formula (1-2) R ^1, R ² and R ³ have the abovementioned meaning and R ⁴ is C 1 -C 7 alkyl in the general formula I-3 R ^1, R ² and R ³ are as defined, with the proviso that R 'is a trifluoromethyl group. The aminobenzoic acid derivatives and pharmaceutically acceptable salts thereof according to claim 1, wherein R ¹ is C 3 -C 8 alkynyl. The aminobenzoic acid derivatives and pharmaceutically acceptable salts thereof according to claim 1, wherein R ² is amino. The aminobenzoic acid derivatives and their pharmaceutically acceptable salts according to claim 1, wherein the aminobenzoic acid derivative is a compound of formula (I) wherein R 'in the formula (I) is cyano (C 1 -C 5) alkyl - (C 1 -C 5) -alkoxy (C 3 -C 8) -cycloalkyl, halo (C 1 -C 5) -alkyl or (C 3 -C 8) -alkynyl, with the proviso that R 1 is not trifluoromethyl. The aminobenzoic acid derivatives and their pharmaceutically acceptable salts according to claim 4, wherein, in the formula (I), R ² is amino. A pharmaceutical composition which is a pharmaceutically acceptable salt of an aminobenzoic acid derivative of the formula (I), (1-2), (1-3), wherein the substituents are as defined in claim 1, or a pharmaceutically acceptable salt thereof. containing a therapeutically effective amount of a pharmaceutically acceptable carrier. 7. A pharmaceutical composition according to claim 6 for the prevention and treatment of diseases in which serotonin antagonism is effective. 8. A pharmaceutical composition according to claim 6 for the prevention and treatment of diseases in which the release of acetylcholine is effective. 9. A pharmaceutical composition according to claim 6 for use in enhancing gastrointestinal function. The pharmaceutical composition of claim 6, which increases gastric emptying function. The pharmaceutical composition of claim 6, which is an antiemetic. The pharmaceutical composition of claim 6, which is ataractic. A pharmaceutical composition according to claim 6 for the prevention and treatment of irritable bowel syndrome. The pharmaceutical composition according to claim 6, which is amnesic symptoms, senile dementia, Alzhei17 Suitable for the treatment and prevention of mer illness or addiction. An aminobenzoic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the aminobenzoic acid derivative is a compound of formula (II) wherein R ¹ represents a C 3-8 alkynyl group, R ² is amino or C 2 -C 5 alkanoylamino and R ³ is halogen. 16. The aminobenzoic acid derivative and the pharmaceutically acceptable salts thereof according to claim 1, wherein the aminobenzoic acid derivative is a compound of formula (1-2) or (1-3). 17. The pharmaceutically acceptable salts of the aminobenzoic acid derivatives (1-2-1) or (1-3-1) or the amino benzoic acid derivatives (1-3-1). A process for the preparation of a compound of formula (I) wherein R ¹ , R ² and R ³ are as defined in claim 1, and pharmaceutically acceptable salts thereof, wherein a compound of formula (I) wherein R ² is amino is a compound of Formula (a) wherein R ³ is as defined in Claim 1 and R ⁵ is C 3 -C 8 alkynyl, cyano (C 1 -C 5 alkyl), C 1 -C 5 alkyl substituted by halogen, or C 1 -C 5 alkyl. C3-C8 cycloalkyl substituted with alkoxy, provided that it is not trifluoromethyl; or the reactive derivative thereof is condensed with a compound of formula IX and, if desired, the resulting compound of formula I is converted into a pharmaceutically acceptable salt thereof.